Reply to Watchorn et al.: Asthma Exacerbations in Individuals on Glucagon-like Peptide-1 Receptor Agonists for Type 2 Diabetes.

From the Authors:

We appreciate the insightful comments by Watchorn and colleagues in response to our report on the association between asthma exacerbations and GLP-1RA (glucagon-like peptide-1 receptor agonist) use in patients with comorbid asthma and type 2 (T2) diabetes mellitus (T2DM) (1). The intersection of metabolic disease and asthma is a complex and compelling area of study with direct implications for treatment strategies (2) and clinical outcomes (3). Increasingly, work is being done to try to disentangle the confounding effects of body mass index, insulin resistance, and other features of the metabolic syndrome (which also increase the likelihood of cardiovascular disease) in asthma (4). Inclusion of atherosclerotic cardiovascular disease (defined as ≥1 International Classification of Diseases, ninth edition, or International Classification of Diseases, tenth edition, codes) as a variable in our model did not change the primary outcome, as follows: counts of asthma exacerbations in all comparator groups remained significantly (P ≤ 0.05) higher than in the GLP-1RA user group. Atherosclerotic cardiovascular disease was also not a significant predictor (P = 0.97) in the primary outcome model. This is consistent with the clinical context, as asthma symptoms (secondary outcome) may be nonspecific, but asthma exacerbations (defined as corticosteroid prescriptions) may be far less so.

Importantly, the authors also raise the question of mechanism as it relates to the heterogeneity of asthma phenotypes on the inflammatory spectrum. Our study cohort was comprised of adults with asthma and T2DM, with a mean body mass index ranging from 34 to 39, clinical characteristics associated with non-T2 asthma (5). In a lean murine model of allergic airway inflammation, the GLP-1RA liraglutide inhibited T2-inflammation pathways (6). Additional preclinical and clinical investigations are underway in our research groups to determine the actions of GLP-1R agonists in T2 and non-T2 airway inflammation. Obese asthma models and patient-oriented biomarker studies would be helpful in providing additional insight to the question of mechanism and would inform the design of prospective studies. Our retrospective observational study was conducted within the context of routine care and was not designed to compare the effects of GLP-1 analogs with exendin-based GLP-1 agents, which would require much larger sample sizes (particularly for detection of a rare outcome) or a prospective study.

In conclusion, Watchorn and colleagues’ letter highlights the need for prospective studies of GLP-1RA therapy using single agents within the class (e.g., GLP-1 analogs or exendin-based therapies) in well-phenotyped asthma populations with outcomes aligned with regulatory approval metrics—we absolutely agree, and we look forward to this unfolding area of investigation.